Early life sleep disruption drives lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

AbstractSleep disruption is a common comorbidity in patients with autism spectrum disorder (ASD), a condition diagnosed with a striking male bias of ∼4:1. It is unclear how sleep disruption contributes to ASD susceptibility, and the sex biased vulnerability. We examined sleep behavior and the effects of early life sleep disruption (ELSD) in developing mice bearing C-terminal truncation (ΔC) in ASD risk gene Shank3. Male and female Shank3ΔC/ΔC homozygotes showed clear sleep disruption early in postnatal life, compared to Shank3WT/ΔC heterozygotes and wild-type littermates, suggesting that sleep disruption may be an early symptom in the expression of ASD. We find that ELSD interacts with genetic vulnerability in Shank3WT/ΔC heterozygotes to drive lasting and sex-specific changes in behavior. Our results clearly show that sleep disruption during sensitive periods of postnatal development is causative of lasting changes in behavior in genetically vulnerable individuals, but in a striking sex-specific manner.

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025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

SLEEP ◽

10.1093/sleep/zsab072.024 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A11-A12

Author(s):

Carolyn Jones ◽

Randall Olson ◽

Alex Chau ◽

Peyton Wickham ◽

Ryan Leriche ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Prefrontal Cortex ◽

Early Life ◽

Autism Spectrum ◽

Prairie Vole ◽

Sleep Disruption ◽

Glutamatergic Synapses ◽

The Brain ◽

Orbital Shaker

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

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Maternal approach behaviors toward neonatal calls are impaired by mother’s experiences of raising pups with a risk gene variant for autism

10.1101/2020.05.21.107540 ◽

2020 ◽

Author(s):

Risa Kato ◽

Akihiro Machida ◽

Kensaku Nomoto ◽

Gina Kang ◽

Takeshi Hiramoto ◽

...

Keyword(s):

Genetic Risk ◽

Autism Spectrum ◽

Incentive Motivation ◽

Wild Type ◽

Sequence Structure ◽

Maternal Behaviors ◽

Risk Gene ◽

Mother's Experience ◽

Approach Behaviors ◽

Mouse Pup

AbstractHow the intrinsic sequence structure of neonatal mouse pup ultrasonic vocalization (USV) and maternal experiences determine maternal behaviors in mice is poorly understood. Our previous work showed that pups with a Tbx1 heterozygous (HT) mutation, a genetic risk for autism spectrum disorder (ASD), emit altered call sequences that do not induce maternal approach behaviors in C57BL6/J mothers. Here, we tested how maternal approach behaviors induced by wild-type and HT USVs are influenced by the mother’s experience in raising pups of these two genotypes. The results showed that wild-type USVs were effective in inducing maternal approach behaviors when mothers raised wild-type but not HT pups. The USVs of HT pups were ineffective regardless of whether mothers raised HT or wild-type pups. However, the sequence structure of pup USVs had no effect on the general, non-directional incentive motivation of maternal behaviors. Our data show how the mother’s experience with a pup with a genetic risk for ASD alters the intrinsic incentive values of USV sequences in maternal approach behaviors.

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Titanium Dioxide Presents a Different Profile in Dextran Sodium Sulphate-Induced Experimental Colitis in Mice Lacking the IBD Risk Gene Ptpn2 in Myeloid Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22020772 ◽

2021 ◽

Vol 22 (2) ◽

pp. 772

Author(s):

Javier Conde ◽

Marlene Schwarzfischer ◽

Egle Katkeviciute ◽

Janine Häfliger ◽

Anna Niechcial ◽

...

Keyword(s):

Bone Marrow ◽

Titanium Dioxide ◽

Genetic Risk ◽

Intestinal Inflammation ◽

Sodium Sulphate ◽

Food Additive ◽

Wild Type ◽

Dextran Sodium Sulphate ◽

Risk Gene ◽

The Impact

Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO2) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO2 and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (Ptpn2) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of Ptpn2 in myeloid cells (Ptpn2LysMCre) or their wild type littermates (Ptpn2fl/fl) and exposed to the microparticle TiO2. The impact of Ptpn2 on TiO2 signalling pathways and TiO2-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). Ptpn2LysMCre exposed to TiO2 exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO2 on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in Ptpn2 deficient mice. Moreover, we also found that TiO2 was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor Ptpn2 and the environmental factor TiO2 in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk

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Correction to: Absence of parvalbumin increases mitochondria volume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenotypes

Molecular Autism ◽

10.1186/s13229-020-00404-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lucia Janickova ◽

Karin Farah Rechberger ◽

Lucas Wey ◽

Beat Schwaller

Keyword(s):

Autism Spectrum Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Risk Gene

An amendment to this paper has been published and can be accessed via the original article.

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Early life inorganic lead exposure induces testicular teratoma and renal and urinary bladder preneoplasia in adult metallothionein-knockout mice but not in wild type mice

Toxicology ◽

10.1016/j.tox.2010.06.006 ◽

2010 ◽

Vol 276 (1) ◽

pp. 5-10 ◽

Cited By ~ 20

Author(s):

Erik J. Tokar ◽

Bhalchandra A. Diwan ◽

Michael P. Waalkes

Keyword(s):

Urinary Bladder ◽

Lead Exposure ◽

Knockout Mice ◽

Early Life ◽

Wild Type ◽

Inorganic Lead

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A novel machine learning model to predict autism spectrum disorders risk gene

Neural Computing and Applications ◽

10.1007/s00521-018-3502-5 ◽

2018 ◽

Vol 31 (10) ◽

pp. 6711-6717 ◽

Cited By ~ 3

Author(s):

Murat Gök

Keyword(s):

Machine Learning ◽

Autism Spectrum Disorders ◽

Learning Model ◽

Autism Spectrum ◽

Risk Gene ◽

Machine Learning Model ◽

Spectrum Disorders

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The role of infant nutrition in the global epidemic of non-communicable disease

Proceedings of The Nutrition Society ◽

10.1017/s0029665116000057 ◽

2016 ◽

Vol 75 (2) ◽

pp. 162-168 ◽

Cited By ~ 25

Author(s):

Atul Singhal

Keyword(s):

Early Life ◽

Infant Nutrition ◽

Communicable Disease ◽

Bottle Feeding ◽

Postnatal Life ◽

World Region ◽

Global Epidemic ◽

Main Determinants ◽

The Impact

Non-communicable diseases (NCD) and atherosclerotic CVD in particular, are the most important health problems of the 21st century. Already in every world region except Africa, NCD account for greater mortality than communicable, maternal, perinatal and nutritional conditions combined. Although modifiable lifestyle factors in adults are the main determinants, substantial evidence now suggests that factors in early life also have a major role in the development of NCD; commonly referred to as the Developmental Origins of Health and Disease hypothesis. Factors in utero, early postnatal life and throughout childhood, have been shown to affect NCD by influencing risk factors for CVD such as obesity, diabetes, hypertension and dyslipidaemia. Infant nutrition (e.g. breastfeeding rather than bottle feeding) and a slower pattern of infant weight gain have been shown to be particularly protective against later risk of obesity and CVD in both low- and high-income countries. The mechanisms involved are poorly understood, but include epigenetic changes; effects on endocrine systems regulating body weight, food intake and fat deposition; and changes in appetite regulation. As a consequence, strategies to optimise early life nutrition could make a major contribution to stemming the current global epidemic of NCD. This review will consider the role of early life factors in the development of NCD, focusing on the impact of infant nutrition/growth on obesity and CVD. The review will highlight the experimental (randomised) evidence where available, briefly summarise the underlying mechanisms involved and consider the implications for public health.

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Rel Induces Interferon Regulatory Factor 4 (IRF-4) Expression in Lymphocytes

Journal of Experimental Medicine ◽

10.1084/jem.191.8.1281 ◽

2000 ◽

Vol 191 (8) ◽

pp. 1281-1292 ◽

Cited By ~ 146

Author(s):

Raelene J. Grumont ◽

Steve Gerondakis

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Nuclear Factor Κb ◽

Wild Type ◽

Cell Type ◽

Regulatory Factor ◽

Specific Manner ◽

A Cell ◽

Cell Type Specific ◽

Interferon Regulatory Factor 4

In lymphocytes, the Rel transcription factor is essential in establishing a pattern of gene expression that promotes cell proliferation, survival, and differentiation. Here we show that mitogen-induced expression of interferon (IFN) regulatory factor 4 (IRF-4), a lymphoid-specific member of the IFN family of transcription factors, is Rel dependent. Consistent with IRF-4 functioning as a repressor of IFN-induced gene expression, the absence of IRF-4 expression in c-rel−/− B cells coincided with a greater sensitivity of these cells to the antiproliferative activity of IFNs. In turn, enforced expression of an IRF-4 transgene restored IFN modulated c-rel−/− B cell proliferation to that of wild-type cells. This cross-regulation between two different signaling pathways represents a novel mechanism that Rel/nuclear factor κB can repress the transcription of IFN-regulated genes in a cell type–specific manner.

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Estrogen and testosterone in concert with EFNB3 regulate vascular smooth muscle cell contractility and blood pressure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00873.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. H861-H872 ◽

Cited By ~ 12

Author(s):

Yujia Wang ◽

Zenghui Wu ◽

Eric Thorin ◽

Johanne Tremblay ◽

Julie L. Lavoie ◽

...

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Gene Knockout ◽

Target Cells ◽

Wild Type ◽

Cell Contractility ◽

Risk Gene ◽

Kinase Phosphorylation

EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions, although their function in blood pressure (BP) control has not been studied in detail. In the present study, we report that Efnb3 gene knockout (KO) led to increased BP in female but not male mice. Vascular smooth muscle cells (VSMCs) were target cells for EFNB3 function in BP regulation. The deletion of EFNB3 augmented contractility of VSMCs from female but not male KO mice, compared with their wild-type (WT) counterparts. Estrogen augmented VSMC contractility while testosterone reduced it in the absence of EFNB3, although these sex hormones had no effect on the contractility of VSMCs from WT mice. The effect of estrogen on KO VSMC contractility was via a nongenomic pathway involving GPER, while that of testosterone was likely via a genomic pathway, according to VSMC contractility assays and GPER knockdown assays. The sex hormone-dependent contraction phenotypes in KO VSMCs were reflected in BP in vivo. Ovariectomy rendered female KO mice normotensive. At the molecular level, EFNB3 KO in VSMCs resulted in reduced myosin light chain kinase phosphorylation, an event enhancing sensitivity to Ca2+ flux in VSMCs. Our investigation has revealed previously unknown EFNB3 functions in BP regulation and show that EFNB3 might be a hypertension risk gene in certain individuals.

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